The broad, long-term objective of the proposed project is to improve the prognosis of patients with myocardial ischemia caused by coronary artery disease (CAD) or coronary microvascular dysfunction (CMD). Early diagnosis of myocardial ischemia caused by CAD is important as both coronary revascularization and medical therapies can significantly reduce morbidity and mortality. CMD is a major cause for myocardial ischemia in the absence of obstructive CAD, particularly in women, due to abnormalities in coronary microcirculation. First- pass myocardial perfusion cardiac magnetic resonance (CMR) is a highly promising technique for detecting regional blood flow deficits caused by ischemia. It does not require ionizing radiation and provides higher spatial resolution than nuclear imaging. Dynamic images acquired during intravenous vasodilator stress delineate regions associated with myocardial ischemia. Despite considerable technical improvements and clinical experience, a recent multicenter multivendor study (MR-IMPACT II) shows that while the sensitivity of CMR to detect ischemia caused by CAD is superior to SPECT (67% vs 59%), specificity is inferior (61% vs 72%). Both sensitivity and specificity of CMR remain relatively low indicating substantial false positive and false negative diagnoses. Several studies using MBF CMR have shown that abnormal MBF can be used to detect ischemia caused by CMD. However, these studies have shown only moderate diagnostic accuracy, indicating the need for major improvements. Major technical limitations of MBF CMR that contribute to inaccurate diagnoses of CAD and CMD include: (i) image artifacts, such as dark rim artifact (DRA) and cardiac and respiratory motion-induced artifacts, which reduce the image quality and diagnostic accuracy; (ii) incomplete coverage of the LV for evaluating total ischemic burden; (iii) inadequate spatial resolution for reliable detection of subendocardial perfusion deficits; and (iv) errors in AIF estimation for flow quantification due to saturation of blood signal intensity at pea enhancement. In the proposed project, we will develop novel techniques to address these limitations (Aim 1). The techniques will be rigorously validated in animals using microsphere measurements as the reference (Aim 2). Finally, the techniques will be tested in CAD and CMD patients using PET and invasive coronary reactivity testing as reference, respectively (Aim 3). The end point of the project is the development and rigorous validation of a new myocardial perfusion quantification CMR method with whole-heart coverage, high isotropic resolution, cardiac phase-resolved acquisition, accurate arterial input estimation while without the requirements of ECG triggering or breath-hold. It is expected that such a technique will significantly improve image quality, reduce technical failures, increase the diagnostic accuracy, and facilitate the eventual adoption of myocardial perfusion CMR as the method of choice for detecting myocardial ischemia. .